Sickle cell disease a hemolytic disorder, which affects, in its most severe form, approximately 80,000 patients in the United States (see, for example, D. L. Rucknagel, in R. D. Levere, Ed., Sickle Cell Anemia and Other Hemoglobinopathies, Academic Press, New York, 1975, p. 1). Sickle cell disorders are inherited disorders of the haemoglobin (Hb) in the red blood cells. It includes Sickle Cell Anemia (Hb SS), Hemoglobin SC Disease (Hb SC) and Sickle Beta Thalassaemia (Hb Beta-Thal). Of these, the most common and severe is sickle cell anemia.
Sickle cell anemia is caused by a single mutation in the hemoglobin molecule; β6 glutamic acid in normal adult hemoglobin A is changed to valine in sickle hemoglobin S (Ingram, Nature 1956, 178:792-794). Hemoglobin S has a markedly decreased solubility in the deoxygenated state when compared to that of hemoglobin A. Therefore, upon deoxygenation, hemoglobin S molecules within the erythrocyte tend to aggregate and form helical fibers that cause the red cell to assume a variety of irregular shapes, most commonly in the sickled form. After repeated cycles of oxygenation and deoxygenation, the sickle cell in the circulation becomes rigid and no longer can squeeze through the small capillaries in tissues, resulting in delivery of insufficient oxygen and nutrients to the organ, which eventually leads to local tissue necrosis. The prolonged blockage of microvascular circulation and the subsequent induction of tissue necrosis lead to various symptoms of sickle cell anemia, including painful crises of vaso-occlusion.
Hemoglobin SC disease (Hb SC) and Sickle Beta-Thalassaemia (Hb S-Thal) occur when someone inherits sickle hemoglobin (Hb S) from one of their parents and either hemoglobin C or Beta-Thalassaemia from the other parent. The symptoms of these two conditions are often similar to, but usually less severe than, those of sickle cell anemia.
For most patients, sickle cell anemia does not cause chronic pain. However, most sickle cell anemia patients suffer from sporadic and recurrent episodes that are referred to as painful episodes. Painful episodes typically involve blockade of capillaries and prevention of blood flow into a tissue, which becomes starved of oxygen and glucose. During such crises, a sickle cell (SC) patient will usually experience severe pain at one or more locations, which frequently vary between patients. It is not uncommon for a joint or joints to become swollen and sore. By far the most common type of crisis is the infarctive or painful crisis, characterized by severe skeletal pain which may persist for several days or even weeks. In addition, or alternatively, the patient may suffer from either sharp or diffuse pain in the abdomen, which is presumed to be due to ischemic conditions in one or more organs.
Most sickle cell patients usually suffer several painful episodes per year. The patient usually must be hospitalized for parenteral opioid analgesia, restricted to bed rest with little or no exertion to prevent pathological fracture of potentially infarcted bone, and treated with a variety of drugs, including potent analgesics, such as morphine, codeine, and meperidine (also known as Demerol™), and by broad-spectrum antibiotics, both to help control any infections that may be contributing to the crises, and to help prevent or reduce additional infections in tissues or organs that are weakened by the ischemic crisis. Among hospitalizations including the diagnosis of sickle cell disease, 25% of patients are less than 15 years old.
The physiological damage and increased morbidity and mortality caused by sickle cell anemia has been studied extensively (Platt et al., NEJM 1994, 3 30:1639-1644). Briefly, among young children, dactylitis is common, due to ischemic necrosis of the small bones and cartilages of the hands and feet, and acute abdominal pain is often caused by accumulating damage to the spleen. Acute abdominal pain can also be due to spleen, liver or kidney infarction, or the pain can be simply associated with hematuria.
A treatment for sickle cell anemia that has shown benefit involves a compound called hydroxyurea. In some patients, this compound can reduce the frequency, but not the severity, of sickle cell crises, presumably due to an ability to increase the expression levels of fetal hemoglobin genes. However, this treatment has only limited utility; many patients on hydroxyurea still experience recurrent painful episodes, and it is not effective in treating those episodes.
While several innovative pharmacologic approaches to analgesia in this setting have been suggested, including Nalbuphine (Woods et al., J Assoc Acad Minor Phys 1990, 1(3): 90-2); epidural bupivicaine and intravenous fentanyl (Yaster et al. Pediatrics 1994, 93(2):310-5); high dose methylprednisolone and morphine (Griffin et al., N Engl J Med 1994; 330:733-7); and Piroxicam (Eke et al., Tropical Medicine and International Health 2000, 5:81-84), there is still a need for improved modalities of analgesic care of sickle cell disease (Yaster et al., Peditr Clin North Am 2000; 47: 699-710).
There remains a need for safe and effective methods of pain management for sickle cell patients, including pediatric patients. These and other objects of the invention will become more apparent through the following summary, drawings, and description of the preferred embodiments.